Sponsor Selection Criteria for CDMOs – Part 2 of 3

Equipment Exclusively Allocated to GMP Operations

Regardless of size, many contract manufacturing organizations have dealt with tight resources that limit workers from buying essential tools. However, when research and development (R&D) professionals are left to share GMP production and lab equipment due to limited resources, noncompliance is typically the result. The difficulty is obvious; it makes no difference who operates GMP equipment for all intents and purposes. All GMP products must be traceable, cleaning and swabbing of multiproduct equipment must comply with SOPs, and R&D staff training records must meet the standards of GMP workers. Even for GMP employees, this is a challenging standard to consistently meet, let alone development personnel. During an inspection of an East Coast CDMO, I saw two examples of the difficulties of shared equipment.

The first example involved a sponsor sending samples for HPLC (high-performance liquid chromatography) assay and impurity testing to its CDMO. After being informed that these results were crucial to the start of the sponsor’s clinical investigation, the lab promised to expedite its work and deliver the data to the sponsor within a week. In this case, quality control (QC) took possession of the sample and ran the necessary tests. The QC analyst found the following day that the active peak in both the standards and the samples eluted soon after each injection began (i.e., void volume), rather than considerably later in the chromatogram as was called for by the test procedure. 

It was discovered that the QC analyst’s HPLC and column were utilized by the R&D chemist the day before to process a sample. The HPLC column was compromised because the stationary phase was not compatible with the sample matrix of the R&D sample. Not only did the R&D chemist forget to fill out the QC logs for the HPLC and column usage, but there also were no training records for the HPLC or GMP compliance. The R&D chemist didn’t disclose his mistakes until he overheard the QC analyst discuss the issue with his manager. Since QC didn’t have a replacement HPLC column, they had to place an order with the manufacturer. Both the test results and the beginning of the clinical study were pushed back by four weeks. Had R&D and quality control had their own equipment, this wouldn’t have occurred.

In the second example, CDMO’s GMP multi-product manufacturing facility was involved, and R&D used a piece of coating equipment in its production department to find the ideal tablet weight gain during the coating of an enteric solution. R&D completed the study and cleaned the equipment, but they neglected to fill out the log for equipment use and cleaning and did not collect and submit swab samples to quality control, which would have proven that the active ingredients had been removed and released the equipment for GMP operation.

Manufacturing operators prepared the coater and other machinery for GMP production the day after. All of the equipment was cleared for GMP use after the operators double-checked the cleaning and use records. Then, a worker realized something was off: there wasn’t a “clean” status tag on the equipment. The worker contacted their manager, who speculated that the status tag may have been lost in transit.

The worker reached out to QA for clarification. A “clean” status tag was securely fastened to the gear with a plastic cable tie, as evidenced by the company’s records, would not have likely to come loose on its own. Realizing the oddity of the situation the worker called the R&D supervisor, who then revealed that her team had utilized the coater for an R&D project without completing logs or doing cleaning verification. The worker’s attention to detail prevented the coater from being reused in the subsequent GMP production, which could have resulted in product contamination.

The Importance of Having Backup Equipment

CDMOs frequently hear complaints about their lack of backup equipment (i.e., same brand and model). For smaller businesses, this is especially true across all dosage forms. Inevitably, there will be a breakdown in the equipment, and it will happen exactly when you need it most. The lack of a  backup strategy will stop the production of the sponsor’s product dead in its tracks.

Sponsors should consider the following issues before committing to a contract with a CDMO for product manufacture. Does the CDMO have a backup of the same model and brand of crucial equipment in the event of a breakdown? Will the equipment set points remain the same, and if not, how should they be adjusted if only a different manufacturer’s/equipment model’s is available? Does the CDMO have a documented backup plan ready to go into effect when (not if) the custom-built equipment fails?

A sponsor I worked with selected a CDMO for its powder micro-dosing capabilities. When active pharmaceutical ingredients (APIs) are in short supply and precise weighing of extremely small dosages is necessary, a one-of-a-kind equipment may be an invaluable asset for automating the dispensing of APIs into capsules. A bigger automated capsule filler would have been ideal for the clinical investigation, but with only 10,000 units at 1 mg per capsule, it was not feasible due to the waste of API during equipment startup.

Unfortunately, not long after production began, the equipment broke down. Upon contact from the CDMO, the equipment manufacturer was able to identify the faulty equipment part on a call but claimed it would take six to eight weeks for a replacement part. The CDMO’s backup plan was to use other capsule filling machines that were manually operated by production technicians. However, the 1 mg dosage was too small to be weighed effectively by hand, in addition to the 10,000 units needed. The project was paused until the replacement part arrived. It is possible that the product lot would have been manufactured and delivered to the sponsor’s clinical site on time had the CDMO had backup equipment/parts.